A major issue in neuroscience is how networks of neurons generate complex behaviors responsible for sustained health and well being; the neural control system for breathing is one such network. Evidence over the past decade suggests that the pre- Botzinger Complex (pBC), a bilaterally distributed subregion of the ventrolateral medulla, contains a region of the brainstem important for respiratory rhythm generation. The objective of this application is to develop computational models to elucidate mechanisms for rhythm generation at the level of the pBC in the transverse slice. The rationale for this particular project is that an ultimate understanding of how intrinsic and synaptic cellular properties contribute to the generation and control of respiratory rhythmogenesis is required to understand the neural control of breathing in vivo, in both physiological and pathophysiological states. Computational approaches are particularly useful for this investigation because the single cell and network dynamics are complex and difficult to analyze mechanistically by experimental approaches alone. We are particularly well prepared to undertake this proposed research, since we previously formulated minimal computational models of pBC rhythm generation, have developed and are continuing to develop more complex ion-channel based models of neurons in the transverse slice, and have an active collaborative relationship with a leading experimental laboratory in this field. The aims of this proposal are 1) Investigate multiple mechanisms for excitatory- coupling based rhythm generation that depend on both intrinsic ion channel as well as synaptic properties. 2) Development of comprehensive ion channel models of the major respiratory-related neuron types in the transverse slice, including the pBC neurons, pre- motor neurons, hypoglossal neurons, and minimal models of raphi and tonic neurons providing critical baseline modulatory input to the pBC neurons. 3) Integrate the model types from Aim 2 into a comprehensive transverse slice model that includes a complete pathway from raphi to pBC to premotor to motoneuron. Our approach is innovative in that our continuing philosophy is to pursue this approach methodically, from the bottom up, i.e. starting with the transverse. Besides the relevance to respiratory physiology, our results will also contribute in general to a growing body of knowledge on general mechanisms of stable rhythm generation from neural populations.